Antibacterial agents

ABSTRACT

Naphthyridine and quinoline derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.

This application is a continuation of U.S. application Ser. No.11/814,611, filed Jul. 24, 2007 now U.S. Pat. No. 7,511,035, which is anational stage entry of PCT/US2006/002617, filed Jan. 24, 2006, whichclaims the benefit of U.S. Provisional Application No. 60/646,813, filedJan. 25, 2005.

FIELD OF THE INVENTION

This invention relates to novel compounds, compositions containing them,their use as antibacterials, and processes for their preparation.

BACKGROUND OF THE INVENTION

The emergence of pathogens resistant to known antibiotic therapy isbecoming a serious global healthcare problem (Chu, et al., (1996) J.Med. Chem., 39: 3853-3874). Thus, there is a need to discover new broadspectrum antibiotics useful in combating multidrug-resistant organisms.Importantly, it has now been discovered that certain compounds haveantibacterial activity, and, therefore, may be useful for the treatmentof bacterial infections in mammals, particularly in humans. WO0125227,WO0240474, WO0207572, WO04024712, WO04024713, WO9937635, WO0021948,WO0021952, WO0043383, WO0078748, WO0107433, WO0107432, WO0208224,WO0224684, WO0250061, WO0250040, WO0256882, WO0296907, WO03087098,WO03010138, WO03064431, WO03064421, WO04002992, and WO0400249 disclosequinoline and/or naphthyridine derivatives having antibacterialactivity.

SUMMARY OF THE INVENTION

This invention comprises compounds of the formula (I), as describedhereinafter, which are useful in the treatment of bacterial infections.This invention is also a pharmaceutical composition comprising acompound according to formula (I) and a pharmaceutically acceptablecarrier. This invention is also processes for the preparation ofcompounds of formula (I), as well as processes for the preparation ofintermediates useful in the synthesis of compounds of formula (I). Thisinvention is also a method of treating bacterial infections in mammals,particularly in humans.

DETAILED DESCRIPTION OF THE INVENTION

In some embodiments, this invention describes a compound of formula (I)

wherein:

Z is CH or N;

R is hydrogen or F;

W₃ is CH; C(OH); or N;

W₁, W₂, W₄, and W₅ are CH₂; or

one of W₁, W₂, W₄, and W₅ is C═O and the others are CH₂;

A is CH₂ or CH(OH);

R₁ is 4H-Pyrido[3,2-b][1,4]thiazin-3-oxo-6-yl;4H-Pyrido[3,2-b][1,4]oxazin-3-oxo-6-yl; or2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl; or

a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, this invention describes a compound of formula (I)wherein Z is N.

In some embodiments, this invention describes a compound of formula (I)wherein R is F.

In some embodiments, this invention describes a compound of formula (I)wherein W₃ is N.

In some embodiments, this invention describes a compound of formula (I)wherein W₃ is CH₂.

In some embodiments, this invention describes a compound of formula (I)wherein W₃ is CH(OH).

In some embodiments, this invention describes a compound according toformula (I) wherein W₁, W₂, W₄, and W₅ are CH₂.

In some embodiments, this invention describes a compound according toformula (I) wherein one of W₁, W₂, W₄, and W₅ is C═O.

In some embodiments, this invention describes a compound of formula (I)wherein the compound is6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,6-{[(2-{4-[3-fluoro-6-(methyloxy)-4-quinolinyl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,4-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone,6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,4-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone,6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,1-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone,6-{[(2-{1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,6-{[(2-{1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-piperidinylethyl}amino]methyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-hydroxy-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-hydroxy-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,or6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-piperidinyl}-2-hydroxyethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one,or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, this invention describes a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier.

In some embodiments, this invention describes a method of treatingbacterial infections in mammals which comprises administering to amammal in need thereof an effective amount of a compound according toformula (I).

Unless otherwise defined, the term “alkyl” when used alone or whenforming part of other groups (such as the ‘alkoxy’ group) includessubstituted or unsubstituted, straight or branched chain alkyl groupscontaining the specified range of carbon atoms. For example, the term“(C₁₋₆)alkyl” include methyl, ethyl, propyl, butyl, iso-propyl,sec-butyl, tert-butyl, iso-pentyl, and the like.

The term “alkenyl” means a substituted or unsubstituted alkyl group ofthe specified range of carbon atoms, wherein one carbon-carbon singlebond is replaced by a carbon-carbon double bond. For example, the term“(C₂₋₆)alkenyl” include ethylene, 1-propene, 2-propene, 1-butene,2-butene, and isobutene, and the like. Both cis and trans isomers areincluded.

The term “cycloalkyl” refers to substituted or unsubstituted carbocyclicsystem of the specified range of carbon atoms, which may contain up totwo unsaturated carbon-carbon bonds. For example, the term“(C₃₋₇)cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, and cycloheptyl.

The term “alkoxy” refers to an O-alkyl radical where the alkyl groupcontains the specified range of carbon atoms and is as defined herein.

The term “acyl” refers to a C(═O)alkyl or a C(═O)aryl radical. In someembodiments, the alkyl group contains 13 or less carbons; in someembodiments 10 or less carbon atoms; in some embodiments 6 or lesscarbon atoms; and is as otherwise defined. Aryl is as defined herein.

The term “alkylcarbonyl” refers to a (C₁₋₆)alkyl(C═O)(C₁₋₆)alkyl groupwherein alkyl is as otherwise defined herein.

The term “alkylsulphonyl” refers to a SO₂alkyl radical wherein the alkylgroup contains the specified range of carbon atoms and is as definedherein.

The term “alkylthio” refers to a Salkyl wherein the alkyl group containsthe specified range of carbon atoms and is as defined herein.

The term “aminosulphonyl” refers to a SO₂N radical wherein the nitrogenis substituted as specified.

The term “aminocarbonyl” refers to a carboxamide radical wherein thenitrogen of the amide is substituted as defined.

The term “heterocyclylthio” refers to a S-heterocyclyl radical whereinthe heterocyclyl moiety is as defined herein.

The term “heterocyclyloxy” refers to an O-heterocyclyl radical whereinheterocyclyl is as defined herein.

The term “arylthio” refers to an S-aryl radical wherein aryl is asdefined herein.

The term “aryloxy” refers to an O-aryl radical wherein aryl is asdefined herein.

The term “acylthio” refers to a S-acyl radical wherein acyl is asdefined herein.

The term “acyloxy” refers to an O-acyl radical wherein acyl is asdefined herein.

The term “alkoxycarbonyl” refers to a CO₂alkyl radical wherein the alkylgroup contains the specified range of carbon atoms and is as definedherein.

The term “alkenyloxycarbonyl” refers to a CO₂alkyl radical wherein thealkenyl group contains the specified range of carbon atoms and is asdefined herein.

The term “alkylsulphonyloxy” refers to an O—SO₂alkyl radical wherein thealkyl group contains the specified range of carbon atoms and is asdefined herein.

The term “arylsulphonyl” refers to a SO₂aryl radical wherein aryl is asherein defined.

The term “arylsulphoxide” refers to a SOaryl radical wherein aryl is asdefined herein.

Unless otherwise defined, suitable substituents for any alkyl, alkoxy,alkenyl, and cycloalkyl groups includes up to three substituentsselected from the group consisting of hydroxy, halogen, nitro, cyano,carboxy, amino, amidino, sulphonamido, unsubstituted (C₁₋₃)alkoxy,trifluoromethyl, and acyloxy.

Halo or halogen includes fluoro, chloro, bromo and iodo.

The term “haloalkyl” refers to an alkyl radical containing the specifiedrange of carbon atoms and is as otherwise defined herein, which isfurther substituted with 1-3 halogen atoms.

The term “haloalkoxy” refers to an alkoxy radical of the specified rangeand as defined herein, which is further substituted with 1-3 halogenatoms.

The term “hydroxyalkyl” refers to an alkyl group as defined herein,further substituted with a hydroxy group.

Unless otherwise defined, the term “heterocyclic” or “heterocyclyl” asused herein includes optionally substituted aromatic and non-aromatic,single and fused, mono- or bicyclic rings suitably containing up to fourhetero-atoms in each ring selected from oxygen, nitrogen and sulphur,which rings may be unsubstituted or C-substituted by, for example, up tothree groups selected from (C₁₋₄)alkylthio; halo; (C₁₋₄)haloalkoxy;(C₁₋₄)haloalkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy; hydroxy,(C₁₋₄)alkyl; (C₁₋₄)thioalkyl; (C₁₋₄)alkoxy; nitro; cyano, carboxy;(C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonyl whereinthe amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl.

Each heterocyclic ring suitably has from 3 to 7, preferably 5 or 6, ringatoms. A fused heterocyclic ring system may include carbocyclic ringsand need include only one heterocyclic ring.

Compounds within the invention containing a heterocyclyl group may occurin two or more tautometric forms depending on the nature of theheterocyclyl group; all such tautomeric forms are included within thescope of the invention.

Where an amino group forms part of a single or fused non-aromaticheterocyclic ring as defined above suitable optional substituents insuch substituted amino groups include hydrogen; trifluoromethyl;(C₁₋₄)alkyl optionally substituted by hydroxy, (C₁₋₄)alkoxy,(C₁₋₄)alkylthio, halo or trifluoromethyl; and (C₂₋₄)alkenyl.

The term “heterocyclylalkyl” refers to a (C₁₋₆)alkyl radical which bearsas a substituent a heterocyclyl group, wherein heterocyclyl and alkylare as herein defined. The heterocyclyl group maybe joined to a primary,secondary or tertiary carbon of the (C₁₋₆)alkyl chain.

When used herein the term “aryl”, includes optionally substituted phenyland naphthyl.

Aryl groups may be optionally substituted with up to five, preferably upto three, groups selected from (C₁₋₄)alkylthio; halo; (C₁₋₄)haloalkoxy;(C₁₋₄)haloalkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy;(C₁₋₄)hydroxyalkyl; (C₁₋₄)alkylthio; (C₁₋₄)alkoxy; nitro; cyano;carboxy; amino or aminocarbonyl optionally substituted by (C₁₋₄)alkyl;(C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl.

The term “aralkyl” refers to a (C₁₋₆)alkyl radical which bears as asubstituent an aryl group, wherein aryl and alkyl are as herein defined.The aryl group maybe joined to a primary, secondary or tertiary carbonof the (C₁₋₆)alkyl chain.

This invention also contemplates that some of its structural embodimentsmaybe present as a solvate. Solvates maybe produced from crystallizationfrom a given solvent or mixture of solvents, inorganic or organic.Solvates may also produced upon contact or exposure to solvent vapors,such as water. This invention includes within its scope stoichiometricand non-stoichiometric solvates including hydrates.

Furthermore, it will be understood that phrases such as “a compound ofFormula I or a pharmaceutically acceptable salt, solvate or derivativethereof” are intended to encompass the compound of Formula I, aderivative of formula (I), a pharmaceutically acceptable salt of thecompound of formula (I), a solvate of formula (I), or anypharmaceutically acceptable combination of these. Thus by way ofnon-limiting example used here for illustrative purpose, “a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof” mayinclude a pharmaceutically acceptable salt of a compound of formula (I)that is further present as a solvate.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach provided in substantially pure form, for example at least 60% pure,more suitably at least 75% pure and preferably at least 85%, especiallyat least 98% pure (% are on a weight for weight basis). Impurepreparations of the compounds may be used for preparing the more pureforms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of the formula(I) or pharmaceutically acceptable derivative thereof.

Pharmaceutically acceptable salts of the above-mentioned compounds offormula (I) include the free base form or their acid addition orquaternary ammonium salts, for example their salts with mineral acidse.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acids,or organic acids, e.g. acetic, fumaric, succinic, maleic, citric,benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acidor tartaric acids. Compounds of formula (I) may also be prepared as theN-oxide. Compounds of formula (I) having a free carboxy group may alsobe prepared as an in vivo hydrolysable ester. The invention extends toall such derivatives. One of skill in the art will recognize that wherecompounds of the invention contain multiple basic sites, a compound ofthe invention maybe present as a salt complexed with more than oneequivalent of a corresponding acid or mixture of acids.

Pharmaceutically acceptable derivatives refers to compounds of formula(I) that have been covalently modified with a group that undergoes atleast some in vivo cleavage to a compound of formula (I).

Examples of suitable pharmaceutically acceptable in vivo hydrolysableester-forming groups include those forming esters which break downreadily in the human body to leave the parent acid or its salt.

Suitable groups of this type include those of part formulae (i), (ii),(iii), (iv) and (v):

wherein R^(a) is hydrogen, (C₁₋₆) alkyl, (C₃₋₇) cycloalkyl, methyl, orphenyl, R^(b) is (C₁₋₆) alkyl, (C₁₋₆)alkoxy, phenyl, benzyl,(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyloxy, (C₁₋₆)alkyl(C₃₋₇) cycloalkyl,1-amino(C₁₋₆)alkyl, or

1-(C₁₋₆ alkyl)amino(C₁₋₆) alkyl; or R^(a) and R^(b) together form a1,2-phenylene group optionally substituted by one or two methoxy groups;R^(c) represents (C₁₋₆)alkylene optionally substituted with a methyl orethyl group and R^(d) and R^(e) independently represent (C₁₋₆) alkyl;R^(f) represents (C₁₋₆) alkyl; R^(g) represents hydrogen or phenyloptionally substituted by up to three groups selected from halogen,(C₁₋₆) alkyl, or (C₁₋₆) alkoxy; Q is oxygen or NH; R^(h) is hydrogen or

(C₁₋₆) alkyl; R^(i) is hydrogen, (C₁₋₆) alkyl optionally substituted byhalogen, (C₂₋₆) alkenyl, (C₁₋₆)alkoxycarbonyl, aryl or heteroaryl; orR^(h) and R^(i) together form (C₁₋₆) alkylene; R^(j) representshydrogen, (C₁₋₆) alkyl or (C₁₋₆)alkoxycarbonyl; and R^(k) represents(C₁₋₈)alkyl, (C₁₋₈)alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkoxy or aryl.

Examples of suitable in vivo hydrolysable ester groups include, forexample, acyloxy(C₁₋₆)alkyl groups such as acetoxymethyl,pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl,1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl;(C₁₋₆)alkoxycarbonyloxy(C₁₋₆)alkyl groups, such asethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl andpropoxycarbonyloxyethyl; di(C₁₋₆)alkylamino(C₁₋₆)alkyl especiallydi(C₁₋₄)alkylamino(C₁₋₄)alkyl groups such as dimethylaminomethyl,dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;2-(C₁₋₆)alkoxycarbonyl)-2-(C₂₋₆)alkenyl groups such as2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl;lactone groups such as phthalidyl and dimethoxyphthalidyl.

A further suitable pharmaceutically acceptable in vivo hydrolysableester-forming group is that of the formula:

wherein R^(k) is hydrogen, C₁₋₆ alkyl or phenyl.

R is preferably hydrogen.

Compounds of formula (I) may also be prepared as the correspondingN-oxides.

Certain of the compounds of formula (I) may exist in the form of opticalisomers, e.g. diastereoisomers and mixtures of isomers in all ratios,e.g. racemic mixtures. The invention includes all such form, includingpure isomeric forms. The different isomeric forms may be separated orresolved one from the other by conventional methods, or any given isomermay be obtained by conventional synthetic methods or by stereospecificor asymmetric syntheses.

One of skill in the readily appreciates that optimization for a givenreaction may require some routine variation in reaction parameters suchas reaction time, temperature, energy source, pressure, light, pressure,solvent or solvents used, co-reagents, catalysts, and the like.

Protective groups wherever found herein maybe designated by theirspecific formula or alternatively, maybe referred to generically by P orP_(n) (wherein n is an integer). It is to be appreciated that wheregeneric descriptors are used, that such descriptors are at eachoccurrence independent from each other. Thus, a compound with more thanone of the same generic descriptors (e.g. P) does not indicate that eachP is the same protective group, they maybe the same or different, solong as the group is suitable to the chemistry being employed. Whereprotection or deprotection is generically referred to, one of ordinaryskill in the art will understand this to mean that suitable conditionsare employed that will allow for the removal of the protecting group tobe removed while minimizing reaction at other positions of the molecule,unless otherwise indicated. Many protective groups and protective groupstrategies are known to those of skill in the art in maybe found innumerous references including, Greene, et al. “Protective Groups inOrganic Synthesis” (Published by Wiley-Interscience), which is hereinincorporated by reference in its entirety.

Leaving groups wherever found herein maybe designated by a specificchemical formula, or alternatively, maybe generically referred to as Lor Ln (wherein n is an integer). It is to be appreciated that where ageneric descriptor is used, that such descriptors are at each occurrenceindependent from each other. Leaving groups can be single atoms such asCl, Br, or I, or maybe a group such as OSO₂CH₃, OC(═O)CH₃, O(C═O)CF₃,OSO₂CF₃, and the like. Leaving groups may be formed during the course ofa reaction and thus a compound containing a leaving group may not alwaysbe an isolated material but rather as a reactive intermediate. By way ofnon-limiting example, a carboxylic acid maybe reacted with a couplingreagent such as DCC, CDI, EDCI, isobutyl chloroformate, etc, and thecorresponding reative intermediate thus formed is further reacted withthe nucleophilic coupling partner. In such cases, one of skill in theart appreciates that the activation step maybe performed before theintroduction of the nucleophilic coupling partner, or in some cases,even in the presence of the nucleophilic coupling partner (dependingupon the identity of the particular activating agent, carboxylic acidand nuclephilic coupling partner used). One skilled in the art readilyascertains that leaving groups generally refer to atoms or groups whichcan be eliminated, substituted or otherwise dissociate during the courseof the reaction.

The antibacterial compounds according to the invention may be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other antibacterials.

The pharmaceutical compositions of the invention include those in a formadapted for oral, topical or parenteral use and may be used for thetreatment of bacterial infection in mammals including humans.

The composition may be formulated for administration by any route. Thecompositions may be in the form of tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

The compound of formula (I) may be the sole therapeutic agent in thecompositions of the invention or a combination with otherantibacterials. If the other antibacterial is a β-lactam then aβ-lactamase inhibitor may also be employed.

Compounds of formula (I) are active against a wide range of organismsincluding both Gram-negative and Gram-positive organisms.

The compounds of this invention may also be used in the manufacture ofmedicaments useful in treating bacterial infections in humans or othermammals.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference (whether specifically stated to be so or not) as if eachindividual publication were specifically and individually indicated tobe incorporated by reference herein as though fully set forth.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form, forexample, of product, composition, process, or use claims.

The following examples illustrate the preparation of certain compoundsof formula (I) and the activity of certain compounds of formula (I)against various bacterial organisms. Although specific examples aredescribed in the schemes, one of skill in the art appreciates that themethods are more generally applicable.

One of skill in the art readily appreciates that although the followingschemes describe specific examples, they maybe more generally applied toproduce additional embodiments of this invention. Furthermore, theexamples set forth below are illustrative of the present invention andare not intended to limit, in any way, the scope of the presentinvention.

The compounds of the present invention were prepared by the methodsillustrated in Scheme I. Central linker units were either commerciallyavailable or prepared according to literature reports unless otherwisenoted in the experimental section.

Reagents and conditions: (a)8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine, rac-Binap, Cs₂CO₃, Pd₂dba₃, 18-C-6, dioxane, 100° C., sealed tube (b) 4M HCl in dioxane, MeOH,25° C. (c)3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, Na₂SO₄,DCM/MeOH, 25° C. then Na(OAc)₃BH.

An appropriate amine containing central linker (I) was coupled to anaromatic bromide (II) or equivalent using standard Buchwald conditions.The Boc-protecting group was removed using conditions described byprotecting group references like Kocienski or Greene, infra. Theresulting free amine (III) underwent reductive amination with a suitablearomatic aldehyde generating final analog (IV).

General

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded at 400MHz, and chemical shifts are reported in parts per million (δ) downfieldfrom the internal solvent standard CHCl₃ or MeOH. Abbreviations for NMRdata are as follows: s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, dd=doublet of doublets, dt=doublet of triplets,app=apparent, br=broad. J indicates the NMR coupling constant measuredin Hertz. CDCl₃ is deuterochloroform and CD₃OD is tetradeuteromethanol.Mass spectra were obtained using electrospray (ES) ionizationtechniques. All temperatures are reported in degrees Celsius. E. MerckSilica Gel 60 F-254 thin layer plates were used for thin layerchromatography. Flash chromatography was carried out on E. MerckKieselgel 60 (230-400 mesh) silica gel. Analytical HPLC was performed onBeckman chromatography systems. Preparative HPLC was performed usingGilson chromatography systems. ODS refers to an octadecylsilylderivatized silica gel chromatographic support. YMC ODS-AQ® is an ODSchromatographic support and is a registered trademark of YMC Co. Ltd.,Kyoto, Japan. PRP-1® is a polymeric (styrene-divinylbenzene)chromatographic support, and is a registered trademark of Hamilton Co.,Reno, Nev. Celite® is a filter aid composed of acid-washed diatomaceoussilica, and is a registered trademark of Manville Corp., Denver, Colo.

Preparation 1

Preparation of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (a)(2-[(6-Methoxypyridin-3-ylamino)methylene]malonic Acid Diethyl Ester

A solution of 5-amino-2-methoxypyridine (Aldrich, 100 g, 0.806 mole) anddiethyl ethoxymethylenemalonate (Aldrich, 163 mL, 0.806 mole) in EtOH (1L) was heated at reflux for 4 h, then was cooled to RT. Concentration todryness gave the title compound (238 g, quantitative).

(b) 6-Methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic AcidEthyl Ester

Dowtherm A (Fluka, 500 mL) was brought to boiling (250° C.) in a 2 L3-neck flask fitted with a still-head and a reflux condenser.2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100g, 0.34 mole) was added portion-wise over 5 min. The solution was heatedat reflux for an additional 15 min, allowing some solvent to distilover. The resulting solution was cooled to room temperature and dilutedwith hexane (750 mL). The mixture was cooled in ice for 1 h, then thebrown solid was filtered off, washed with hexane, and dried under vacuumto afford the title compound (61.72 g, 73%).

(c) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic Acid Ethyl Ester

A suspension of6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethylester (74.57 g, 300 mmol) in dry DMF (260 mL) under argon was stirredefficiently* in a water bath (to maintain approximately roomtemperature—may need slight ice-cooling on a large scale). Phosphorustribromide (30.0 mL, 316 mmol) was added dropwise over 15 min andstirring was continued for an additional 30 min. Water (1 L) was added,followed by saturated sodium carbonate solution to pH 7. The solid wascollected by suction filtration, washed with water and dried undervacuum over phosphorus pentoxide to give the title compound (83.56 g,90%).

(d) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic Acid

2 N NaOH (300 mL, 600 mmol) was added dropwise over 30 min to a stirredsolution of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethylester (83.56 g, 268 mmol) in THF (835 mL). Stirring was continuedovernight, at which time LC/MS showed that the saponification wascomplete. 2 N HCl was added to pH 6 and the THF was removed in vacuo. 2N HCl was added to pH 2, then water (250 mL) was added, and the mixturewas cooled thoroughly in ice. The solid was collected by suctionfiltration, washed with water and dried (first using a rotary evaporatorat 50° C. and then under high vacuum at 50° C. overnight) to give thetitle compound (76.7 g, slightly over quantitative). This material wasused without further purification.

(e) 4-Bromo-6-methoxy-[1,5]naphthyridin-3-ylamine

A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid(50 g, 177 mmol) in dry DMF (600 mL) was treated with triethylamine(222.5 mL, 1.60 mole), tert-butanol (265 mL, 2.77 mole) anddiphenylphosphoryl azide (41.75 mL, 194 mmol). The reaction was stirredunder argon at 100° C. for 1 h, then was cooled to room temperature andconcentrated to low volume. Ethyl acetate and excess aqueous sodiumbicarbonate solution were added, the mixture was shaken, and someinsoluble solid was filtered off. The layers were separated and theorganic phase was washed with water (2×) and dried (MgSO₄).Concentration to dryness gave a crude mixture of4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (minor product) and(4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine)carbamic acid tert-butylester (major product) along with impurities.

Without further purification, this mixture was dissolved in CH₂Cl₂ (150mL) and treated with trifluoroacetic acid (100 mL). The reaction wasstirred for 3 h then was concentrated to dryness. The residue waspartitioned between CHCl₃ and saturated sodium bicarbonate solution andthe layers were separated. The aqueous phase was extracted with CHCl₃,and the combined organic fractions were dried (MgSO₄) and concentratedto low volume. The solid was collected by suction filtration, washedwith a small volume of CHCl₃ and dried under vacuum to afford a firstcrop of the title compound (31.14 g). The filtrate was purified by flashchromatography on silica gel (30% EtOAc in CHCl₃) to afford furthermaterial (2.93 g, total=34.07 g, 76%). Alternatively, the filtrate wasleft at room temperature overnight and then filtered to give a secondcrop of the title compound (2.5 g).

(f) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-diazonium Tetrafluoroborate

A solution of 4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (25.2 g,99.2 mmol) in dry THF (400 mL) was maintained at −5° C. whilenitrosonium tetrafluoroborate (12.9 g, 110 mmol) was added portion-wiseover 30 min (approximately 2 g portions). The reaction was continued foran additional 1 h at −5° C., at which time TLC* and LC/MS indicated thatthe reaction was complete. The orange solid was collected by suctionfiltration, washed with ice-cold THF and dried under vacuum to providethe title compound (31.42 g, 90%).

(g) 4-Bromo-3-fluoro-6-methoxy-[1,5]naphthyridine

A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-diazoniumtetrafluoroborate (31.42 g, 89.0 mmol) in decalin (mixed isomers, 500mL) in a 2 L flask* was heated to 180° C. and held at this temperaturefor 5 min. The mixture was cooled and diluted with CHCl₃ (500 mL, tokeep the product in solution), and the resulting mixture was stirredvigorously for 30 min to break up a black solid by-product. The mixturewas then poured onto a column of silica gel and the column was elutedwith CHCl₃ to remove decalin and then with 3% EtOAc/CHCl₃ to afford thetitle compound (9.16 g, 40%).

(h) 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine

To a solution of 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine (2.0g, 7.81 mmol), potassium carbonate (1.08 g, 7.81 mmol),tetrakis-triphenylphosphine (90 mg, 0.08 mmol) in DME (60 mL) and H₂O(20 mL) was added 2,4,6-trivinylcycloborane-pyridine complex (0.94 g,3.91 mmol). After stirring for 10 h at 85° C. the reaction contents wereconcentrated and the product purified by chromatography (silica, 25%EtOAc in hexane) to give a low melting solid (1.43 g, 90%).

Preparation 2

Preparation of 8-ethenyl-2-(methyloxy)-1,5-naphthyridine

To a solution of 6-(methyloxy)-1,5-naphthyridin-4-yltrifluoromethanesulfonate (from Prep. 2b) (5.0 g, 16.23 mmol) in DME (80mL) and H₂O (40 mL) was added trivinyl boronate (1.96 g, 8.1 mmol),K₂CO₃ (2.23 g, 16.23 mmol) and Pd(PPh₃)₄ (0.19 g, 0.16 mmol). After 3 hat 90° C. under N₂, the reaction solution was concentrated under vacuumand purified on silica (hexane/EtOAc, 4:1) to give the title compound asa yellow oil (2.44 g, 81%): LC/MS (m/z) (ES) 187 (M+H)⁺.

Preparation 3

Preparation of3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (a)Methyl 3-oxo-3,4-di hydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of ethyl 2-mercaptoacetate (1.473 mL) in DMF (48 mL) wasice-cooled and treated with sodium hydride (540 mg of a 60% dispersionin oil). After 1 h methyl 6-amino-5-bromopyridine-2-carboxylate (3 g)(T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was addedand the mixture stirred for 16 h at room temperature. The solution wasdiluted with EtOAc (1 L), washed with water (3×300 mL), dried andevaporated to about 10 mL. The white solid was filtered off and washedwith a little EtOAc to give the ester (0.95 g); LC/MS (APCI⁻) m/z 223([M−H]⁻, 100%).

(b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic Acid

A solution of Methyl3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (788 mg)in dioxan (120 ml)/water (30 mL) was treated dropwise over 2 h with 0.5MNaOH solution (8 mL) and stirred overnight. After evaporation to approx.3 ml, water (5 mL) was added and 2M HCl to pH4. The precipitated solidwas filtered off, washed with a small volume of water and dried undervacuum to give a solid (636 mg); LC/MS (APCI⁻) m/z 209 ([M−H]⁻, 5%),165([M-COOH]⁻, 100%).

(c) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

A solution of3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (500mg) in THF (24 mL) with triethylamine (0.396 mL) was cooled to −10° C.and isobutyl chloroformate (0.339 ml) was added. After 20 minutes thesuspension was filtered through kieselguhr into an ice-cooled solutionof sodium borohydride (272 mg) in water (8 mL), the mixture stirred 30minutes and the pH reduced to 7 with dilute HCl. The solvent wasevaporated and the residue triturated under water. The product wasfiltered and dried under vacuum to give a white solid (346 mg); LC/MS(APCI⁻) m/z 195 ([M−H]⁻, 50%), 165(100%).

(d) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (330 mg)in dichloromethane (30 mL)/THF (30 mL) was treated with manganesedioxide (730 mg) and stirred at room temperature. Further manganesedioxide was added after 1 h (730 mg) and 16 h (300 mg). After a total of20 h the mixture was filtered through kieselguhr and the filtrateevaporated. The product was triturated with EtOAc/hexane (1:1) andcollected to give a solid (180 mg); LC/MS (APCI⁻) m/z 195 ([M−H]⁻, 95%),165 (100%).

Preparation 4

Preparation of 4-ethenyl-3-fluoro-6-(methyloxy)quinoline a)4-Hydroxy-6-methoxy-quinoline-3-carboxylic Acid Ethyl Ester

A solution of 4-methoxyaniline (40 g, 0.32 mole) and diethylethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) washeated at reflux in a flask fitted with side-arm and condenser, andheating was continued until all the ethanol had distilled off (ca. 0.5hr). The solution was cooled and pentane was added to give a stickyprecipitate. The solvents were decanted off and the residue was treatedwith more pentane and allowed to stand overnight. The solid was filteredoff and washed well with pentane to give the title compound (62.4 g;78%, contains traces of Dowtherm A).

b) 4-Bromo-6-methoxy-quinoline-3-carboxylic Acid Ethyl Ester

PBr₃ (64.5 g, 22.5 mL, 0.239 mole) was added dropwise to a stirred, icecold suspension of 4-hydroxy-6-methoxy-quinoline-3-carboxylic acid ethylester (59 g, 0.239 mole) in DMF (750 mL); the temperature rose to 15-20°C. for 30 min and then dropped to ca. 5° C. (the starting materialdissolved fairly quickly and a new solid precipitated out). After 3 hrthe solid was collected, washed sequentially with cold DMF, hexane, andwater, then was dried at 40° C. in vacuo overnight to give the titlecompound (41 g, 78%): LC/MS (ES) m/e 310/312 (M+H)⁺.

c) 4-Bromo-6-methoxyquinoline-3-carboxylic Acid

4-Bromo-6-methoxy-quinoline-3-carboxylic acid ethyl ester (41 g, 0.132mole), partially dissolved in THF (600 mL), was treated dropwise withaqueous 2 M sodium hydroxide (198.4 mL, 0.396 mole). After 24 hr, thereaction was complete by TLC (2% MeOH/CH₂Cl₂). The mixture wasneutralized with 5 M HCl then the THF was removed in vacuo. The residuewas dissolved in water and acidified with 5 M HCl. The solid product wascollected under suction, washed well with water, and dried in vacuo togive the title compound (34 g, 91%) as a white solid: MS (ES) m/e282/284 (M+H)⁺.

d) (4-Bromo-6-methoxy-quinolin-3-yl)-carbamic Acid tert-butyl Ester

To a solution of 4-Bromo-6-methoxyquinoline-3-carboxylic acid (34 g,0.121 mole), triethylamine (141 mL) and tert-butanol (181 mL) in dry DMF(400 mL) was added diphenylphosphoryl azide (36.6 g, 28.6 mL, 0.133mole). The mixture was heated at 100° C. for 1 h (see Note), then cooledand concentrated. The residue was dissolved in CH₂Cl₂ and washed withwater (some insoluble material was removed by filtration). The aqueousphase was extracted with dichloromethane and the combined organics weredried (Na₂SO₄) and concentrated. Chromatography on silica gel (1 kg, 1:1ether/light petroleum ether) gave the carbamate (22.7 g, 53%): MS (ES)m/e 309/311 (M+H)⁺, 354/6.

Further elution with ether gave several mixed fractions then pure3-amino-4-bromo-6-methoxyquinoline (2.0 g, 6.5%): MS (ES) m/e 309/311(M+H)⁺, 254/6.

e) 3-Amino-4-bromo-6-methoxyquinoline

(4-Bromo-6-methoxy-quinolin-3-yl)-carbamic acid tert-butyl ester (22.7g, 0.0643 mole) was dissolved in CH₂Cl₂ (200 mL) and treated withtrifluoroacetic acid (100 mL). After 3.5 hr at RT, the mixture wasconcentrated and the residue was dissolved in water. The solution wasmade basic with aqueous sodium carbonate. The precipitate was filteredoff, washed with water, and dried at 40° C. in vacuo overnight, to givethe title compound (16.46 g, 101%) as a white solid: MS (ES) m/e 254/256(M+H)⁺.

f) 4-Bromo-3-methoxyquinolin-3-yl-diazonium Tetrafluoroborate

3-Amino-4-bromo-6-methoxyquinoline (18.4 g, 0.0727 mole) was dissolvedin dry THF (250 mL) and the solution was cooled to −8° C. (EtOH-icebath). Nitrosonium tetrafluoroborate (9.34 g, 0.08 mole) was added inportions over 10 min, keeping the temperature less than −2° C. Themixture was stirred at −5 to 0° C. for 30 min, then the yellowprecipitate was filtered off and washed sequentially with cold THF andhexane. Drying in vacuo gave the title compound (19.4 g, 76%) aninsoluble orange-yellow solid.

g) 4-Bromo-3-fluoro-6-methoxyquinoline

A well stirred solution of decahydronaphthalene (mixed isomers, 120 mL)was heated to ca. 167-170° C. (internal temperature) and the diazoniumtetrafluoroborate salt (6.0 g) was added portion-wise over 30 sec, whenthe solid turned black. The reaction mixture was immediately cooled andthe decahydronaphthalene was filtered off. The filtrate was saved forfurther processing. The residue was extracted with dichloromethane (3×).Some insoluble material remained. The solution was concentrated and theresidue was chromatographed on silica gel (CH₂Cl₂ then CHCl₃) to givethe title compound (1.1 g) as a white solid: MS (ES) m/e 256/258 (M+H)⁺,Rt=2.65 min. About 4% of a dibromo impurity was present: MS (ES) m/e316/318/320 (M+H)⁺Rt=2.94 min.

The decahydronaphthalene solution was treated with excess ethereal HCland the solid hydrochloride salt was collected and washed with hexane.This was converted to the free base by reaction with aqueous sodiumcarbonate followed by extraction with CH₂Cl₂. This gave additional titlecompound (0.87 g; total yield=1.97 g, 45%).

h) 4-ethenyl-3-fluoro-6-(methyloxy)quinoline

4-Bromo-3,fluoro-6-(methoxy)quinoline (2.3 mmol) in DME (26 mL) underargon, was treated with tetrakis(triphenylphosphine)palladium(0) (0.13g, 0.115 mmol) and the mixture stirred at room temperature for 20minutes. Anhydrous potassium carbonate (0.32 g, 2.3 mmol), water (7 mL),and vinylborane:pyridine complex (see F. Kerins and D O'Shea J. Org.Chem. 2002, 67, 4968-4971) (0.22 g, 0.92 mmol) were added and themixture was heated at 100° C. for 2 hr. It was cooled, diluted withwater and extracted with ether, dried over magnesium sulfate andevaporated to dryness. After work-up the product was chromatographed onsilica gel, eluting with 10% methanol in DCM to afford a white solid(0.44 g, 90%). MS (+ve ion electrospray) m/z 203 (MH+).

Preparation 5

Preparation of3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde a)2-Bromo-5-hydroxy-6-nitropyridine

3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol(400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13mole) was added at room temperature. The mixture was stirred for 30 min,then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was addedslowly. The reaction was stirred at 0° C. for 30 min, then was quenchedwith glacial AcOH (2.5 mL). The solvent was removed in vacuo to affordmaterial (30 g, 96%), which was used without further purification.

MS (ES) m/z 219.0 (M+H)⁺.

b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate

2-Bromo-5-hydroxy-6-nitropyridine (30 g, 0.14 mole) was suspended inacetone (200 ml), and potassium carbonate (39 g, 0.28 mole) was added,followed by ethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction washeated at reflux for 10 hr, then was cooled to room temperature anddiluted with Et₂O. The precipitate was removed by suction filtration,and the filtrate was concentrated in vacuo to afford material (38 g,89%), which was used without further purification; MS (ES) m/z 305.0(M+H)⁺.

c) 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one

Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) wasdissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole)was added. The mixture was mechanically stirred and heated at 90° C. for5 hr, then was cooled to room temperature and diluted with EtOAc (300mL). The mixture was filtered through a pad of silica gel and thefiltrate was concentrated in vacuo and the residue recrystallized fromMeOH (15 g, 52%); MS (ES) m/z 229.0 (M+H)⁺.

d) 6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.0 g, 26.3 mmole) andtrans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in1,4-dioxane (150 mL) and the solution was degassed with argon. (Ph₃P)₄Pd(230 mg, 0.2 mmole) was added, followed by a solution of potassiumcarbonate (6.9 g, 50 mmole) in H₂O (20 mL). The reaction was heated atreflux under argon overnight, then was cooled to room temperature anddiluted with EtOAc (200 mL). The solution was washed sequentially withH₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The solidresidue was purified by flash chromatography on silica gel (5-10%EtOAc/CHCl₃) to afford a solid (2.5 g, 38%).

MS (ES) m/z 253.0 (M+H)⁺.

e) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.2 g, 4.8 mmole) wasdissolved in CH₂Cl₂ (200 mL) and the solution was cooled to −78° C.Ozone was bubbled through the solution with stirring until a pale bluecolor appeared, then the excess ozone was removed by bubbling oxygenthrough the solution for 15 min. Dimethylsulfide (1.76 mL, 24 mmole) wasadded to the solution, and the reaction was stirred at −78° C. for 3 hr,then at room temperature overnight. The solvent was removed in vacuo,and the residue was triturated with Et₂O (50 mL). The collected solidwas washed with additional Et₂O and dried to afford a solid (700 mg,82%).

MS (ES) m/z 179.0 (M+H)⁺.

Preparation 6

Preparation of 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde a)5-Benzyloxy-2-hydroxymethyl-1H-pyridin-4-one

A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojicacid by the method of D. Erol, J. Med. Chem, 1994, 29, 893) (9.7 g, 40mmol), concentrated aqueous (880) ammonia (100 mL), and ethanol (20 mL)was heated to reflux overnight. The mixture was allowed to cool to roomtemperature then filtered. The resultant solid was washed with ether anddried in vacuo (5.9 g); MS (APCI+) m/z 232 (MH+).

b) (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol

A solution of 5-Benzyloxy-2-hydroxymethyl-1H-pyridin-4-one (2 g, 8.7mmol) in water (220 mL) containing sodium hydroxide (17 mmol) washydrogenated over 10% palladium on charcoal (1 g) for 4 hours. Themixture was filtered and evaporated to give a white solid. This solidwas dissolved in N,N-dimethylformamide (8 mL) then treated withpotassium carbonate (2.9 g) and 1,2-dibromoethane (0.6 mL, 7 mmol). Themixture was heated at 85° C. overnight. The cooled mixture wasevaporated onto silica and chromatographed eluting with 10-30% methanolin ethyl acetate affording a white solid (250 mg, 21%); MS (APCI+) m/z168 (MH+).

c) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde

A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol(250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganesedioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered andevaporated affording a white solid (150 mg, 61%); MS (APCI+) m/z 166(MH+).

Example 1

Preparation of6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one(a) 1,1-dimethylethyl(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)carbamate

In a sealed tube, 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine (1.1g, 4.3 mmol), 1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate (1 g,4.3 mmol), Pd₂dba₃ (271 mg, 0.262 mmol), rac-Binap (163 mg, 0.262 mmol),Cs₂CO₃ (2.98 mg, 9.2 mmol) and 18-C-6 (115 mg, 0.436 mmol) in dioxane(22 mL) were combined and flushed with N₂. After 15 min, the tube wassealed and heated to 100° C. while stirring rapidly. After 12 h, thesolution was filtered, concentrated and the residue purified via columnchromatography (silica, 1% MeOH in DCM (1% NH₄OH)) yielding the titlecompound (725 mg, 41%) as an orange oil: LCMS (ES) m/e 406 (M+H)⁺.

(b)(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amine

To a solution of 1,1-dimethylethyl(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)carbamate(725 mg, 1.79 mmol) in MeOH (9 mL) at 25° C. was added dropwise a 4Msolution of HCl in dioxane (3.1 mL, 12.53 mmol). After 12 h, thesolution was concentrated the residue neutralized using excess MPcarbonate resin in DCM affording the free amine which was used withoutfurther purification: LCMS (ES) m/e 306 (M+H)⁺.

(c)6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

To a solution of(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amine(155 mg, 0.508 mmol) in DCM-EtOH (5 mL, 1:1) were added Na₂SO₄ (144 mg,1.02 mmol) and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (99 mg,0.508 mmol). After 12 h at 25° C., the imine was quenched by addition ofNaBH₄ (29 mg, 0.762 mmol) in one portion. After an additional 1 h, thesolution was partitioned between H₂O-DCM. The aqueous phase was washedseveral times with DCM and the combined organic fractions were dried(Na₂SO₄), concentrated and purified by column chromatography (silica, 1%MeOH in DCM (1% NH₄OH)) affording the title compound (73 mg, 30%) as alight yellow solid: LCMS (ES) m/e 484 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ8.46 (d, J=4.8 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H),7.13 (d, J=9.1 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 4.06 (s, 3H), 3.92 (s,2H), 3.83 (bs, 4H), 3.54 (bs, 2H), 2.88 (s, 2H), 2.66-2.72 (m, 6H).

Example 2 Preparation of6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

The title compound (99 mg, 42%) was prepared as a yellow solid accordingto Example 1, except substituting3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (91 mg,0.508 mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 468 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.45 (d, J=4.8 Hz, 1H),8.11 (d, J=9.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.13 (d, J=9.1 Hz, 1H),7.01 (d, J=8.1 Hz, 1H), 4.66 (s, 2H), 4.06 (s, 3H), 3.83 (s, 6H),2.82-2.85 (m, 2H), 2.64-2.71 (m, 6H).

Example 3 Preparation of6-{[(2-{4-[3-fluoro-6-(methyloxy)-4-quinolinyl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

The title compound (59 mg, 28%) was prepared as a yellow solid accordingto Example 1, except substituting4-bromo-3-fluoro-6-(methyloxy)quinoline (1.1 g, 4.36 mmol) for8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine: LCMS (ES) m/e 483(M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.50 (d, J=J=4.5 Hz, 1H), 7.89 (d,J=9.1 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.43 (d, J=2.8, 1H), 7.36 (dd,J=2.9, 6.4 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 3.97 (s, 3H), 3.86 (s, 2H),3.53 (s, 2H), 3.44 (bs, 4H), 2.82-2.85 (m, 2H), 2.67-2.75 (m, 6H).

Example 4 Preparation of6-{[(2-{4-[3-fluoro-6-(methyloxy)-4-quinolinyl]-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

The title compound (76 mg, 36%) was prepared as a yellow solid accordingto Example 1, except substituting4-bromo-3-fluoro-6-(methyloxy)quinoline (1.1 g, 4.36 mmol) for8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (81 mg,0.457 mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 467 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.50 (d, J=4.5 Hz, 1H),7.89 (d, J=9.2 Hz, 1H), 7.43 (d, J=2.8 Hz, 1H), 7.36 (dd, J=2.8, 6.4 Hz,1H), 7.29 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 3.97(s, 3H), 3.83 (s, 2H), 3.44 (bs, 4H), 2.82-2.85 (m, 2H), 2.67-2.74 (m,6H).

Example 5 Preparation of6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

(a) 1,1-dimethylethyl[2-(3-oxo-1-piperazinyl)ethyl]carbamate

To a solution of(4-(2-aminium-ethyl)piperazin-one)(2-hydro-phthalazinate-1,4-dione) [3.4g, 11.1 mmol, prepared according to Howell, R. C.; et. al. Molecules2003, 8, 565.] in THF (60 mL) at 25° C. were added Et₃N (7.8 mL, 55.5mmol) and Boc₂O (3 mL, 11.7 mmol). After 1 h, the solution waspartitioned between H₂O-DCM. The aqueous phase was back-extractedseveral times with additional DCM and the combined organic fractionswere dried (Na₂SO₄), concentrated and purified via column chromatography(silica, 1% MeOH in DCM (1% NH₄OH)) yielding the title compound (875 mg,32%) as a clear oil: LCMS (ES) m/e 244 (M+H)⁺.

(b)6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

The title compound (81 mg, 33%) was prepared as a yellow solid accordingto Example 1, except substituting1,1-dimethylethyl[2-(3-oxo-1-piperazinyl)ethyl]carbamate (875 mg, 3.62mmol) for 1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate: LCMS (ES)m/e 498 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ8.83 (s, 1H), 8.29 (d, J=9.1Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 7.06 (d, J=8.8Hz, 1H), 4.09-4.20 (m, 1H), 4.06 (s, 3H), 3.88 (s, 2H), 3.70-3.79 (m,1H), 3.51 (s, 2H), 3.45-3.49 (m, 1H), 3.39-3.41 (m, 1H), 3.01-3.07 (m,2H), 2.84-2.88 (m, 2H), 2.78-2.80 (m, 2H).

Example 6 Preparation of6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

The title compound (22 mg, 9%) was prepared as a yellow solid accordingto Example 1, except substituting1,1-dimethylethyl[2-(3-oxo-1-piperazinyl)ethyl]carbamate (875 mg, 3.62mmol) for 1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate as well as3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (89 mg,0.498 mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 482 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.82 (s, 1H), 8.28 (d,J=9.1 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.99 (d,J=8.0 Hz, 1H), 4.63 (s, 2H), 4.10-4.15 (m, 1H), 4.05 (s, 3H), 3.83 (s,2H), 3.72-3.74 (m, 1H), 3.45 (AB quart., 2H), 3.00-3.06 (m, 2H),2.76-2.84 (m, 4H).

Example 7 Preparation of4-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone

The title compound was prepared (25 mg, 11%) as a yellow solid accordingto Example 1, except substituting1,1-dimethylethyl[2-(3-oxo-1-piperazinyl)ethyl]carbamate (875 mg, 3.62mmol) for 1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate as well as2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (81 mg, 0.492mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 469 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.85 (d, J=5.4 Hz, 1H),8.29 (d, J=8.1 Hz, 1H), 8.00 (d, J=10.9 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H),6.94 (d, J=4.7 Hz, 1H), 4.25-4.36 (m, 4H), 4.09 (s, 2H), 4.03-4.08 (m,1H), 4.07 (s, 3H), 3.72-3.79 (m, 2H), 3.62-3.74 (m, 1H), 3.18-3.23 (m,1H), 2.91-2.99 (m, 3H), 2.65-2.79 (m, 1H), 2.52-2.61 (m, 1H).

Example 8 Preparation of6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one(a) 1,1-dimethylethyl(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)carbamate

In a sealed tube1,1-dimethylethyl[2-(3-oxo-1-piperazinyl)ethyl]carbamate (1.7 g, 7.02mmol), 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate(2.17 g, 7.02 mmol), Pd₂dba₃ (436 mg, 0.421 mmol), rac-Binap (262 mg,0.421 mmol), Cs₂CO₃ (4.81 g, 14.75 mmol) and 18-C-6 (186 mg, 0.702 mmol)in dioxane (35 mL) were combined and flushed with N₂. After 15 min, thetube was sealed and heated to 100° C. while stirring rapidly. After 12h, the solution was filtered, concentrated and the residue purified viacolumn chromatography (silica, 1% MeOH in DCM (1% NH₄OH)) yielding thetitle compound (1.5 g, 53%) as a burgundy foam: LCMS (ES) m/e 402(M+H)⁺.

(b)4-(2-aminoethyl)-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone

To a solution of 1,1-dimethylethyl(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)carbamate(1.5 g, 3.74 mmol) in MeOH (19 mL) at 25° C. was added dropwise, asolution of HCl in dioxane (6.5 mL, 26.18 mmol, 4M HCl in dioxane).After 12 h, the solution was concentrated and the residue neutralizedwith excess MP carbonate resin affording the free amine (1.1 mg, 98%) asa red oil which was used without further purification: LCMS (ES) m/e 302(M+H)⁺.

(c)6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

To a solution of4-(2-aminoethyl)-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone(168 mg, 0.558 mmol) in DCM-EtOH (6 mL, 5:1) at 25° C. were added Na₂SO₄(158 mg, 1.11 mmol) and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (108 mg,0.558 mmol). After 12 h, Na(OAc)₃BH (177 mg, 0.837 mmol) was added andfollowing an additional 2 h, the solution was partitioned betweenDCM-H₂O. The aqueous phase was extracted several times with DCM and thecombined organic fractions were dried (Na₂SO₄), concentrated andpurified via column chromatography (silica, 1% MeOH in DCM (1% NH₄OH))affording the title compound (100 mg, 37%) as a yellow solid: LCMS (ES)m/e 480 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.81 (d, J=4.7 Hz, 1H), 8.28(d, J=9.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.71 (d, J=4.7 Hz, 1H), 7.28(d, J=9.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.04 (s, 3H), 3.92-3.94 (m,2H), 3.88 (s, 2H), 3.51 (s, 2H), 3.34 (2H), 3.00-3.03 (m, 2H), 2.82-2.84(m, 2H), 2.77-2.79 (m, 2H).

Example 9 Preparation of6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

The title compound (20 mg, 7%) was prepared as an orange solid accordingto Example 8, except substituting3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (118 mg,0.664 mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 464 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.80 (d, J=4.7 Hz, 1H),8.27 (d, J=9.1 Hz, 1H), 7.68 (d, J=4.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H),7.25 (d, J=9.2 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.62 (s, 2H), 4.02 (s,3H), 3.89-3.92 (m, 2H), 3.81 (s, 2H), 3.37 (s, 2H), 2.99-3.01 (m, 2H),2.74-2.82 (m, 4H).

Example 10 Preparation of4-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone

The title compound was prepared as a yellow solid according to Example8, except substituting2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (110 mg, 0.664mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 451 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.81 (d, J=4.8 Hz, 1H),8.27 (d, J=9.1 Hz, 1H), 8.03 (s, 1H), 7.67 (d, J=4.7 Hz, 1H), 7.26 (d,J=9.1 Hz, 1H), 6.99 (s, 1H), 4.36-4.38 (m, 2H), 4.29-4.32 (m, 2H), 4.04(s, 3H), 3.90-3.93 (m, 2H), 3.80 (s, 2H), 3.40 (s, 2H), 2.98-3.01 (m,2H), 2.75-2.80 (m, 4H).

Example 11 Preparation of6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

(a)2-chloro-N,N-bis[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]acetamide

To a solution chloroacetyl chloride (1.2 mL, 15.2 mmol) in DCM (65 mL)at 0° C. was added dropwise a solution of2,2′-(iminodi-2,1-ethanediyl)bis(1H-isoindole-1,3(2H)-dione) (5 g, 13.7mmol) [prepared according to Anelli, P. L.; et. al. J. Org. Chem. 198449, 4197.] and Et₃N (2.5 mL, 17.9 mmol) in DCM (65 mL). After 1 h, thesolution was partitioned between H₂O-DCM and the aqueous phase waswashed several times with DCM. The combined organic fractions were dried(Na₂SO₄), concentrated and purified via column chromatography (silica,5% MeOH in DCM (NH₄OH)) yielding the title compound (5.9 g, 98%) as ayellow foam: LCMS (ES) m/e 440 (M+H)⁺.

(b) 2-[2-(2-oxo-1-piperazinyl)ethyl]-1H-isoindole-1,3(2H)-dione

To a solution of2-chloro-N,N-bis[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]acetamide(2 g, 4.55 mmol) in EtOH (230 mL) was added hydrazine hydrate (213 μL,6.83 mmol). After 12 h at 85° C., the solution was concentrated and theresidue purified via column chromatography (silica, 3% MeOH in DCM (1%NH₄OH)) yielding the title compound (428 mg, 34%) as a yellow foam: LCMS(ES) m/e 274 (M+H)⁺.

(c)2-(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-oxo-1-piperazinyl}ethyl)-1H-isoindole-1,3(2H)-dione

A solution of 6-(methyloxy)-1,5-naphthyridin-4-yltrifluoromethanesulfonate (169 mg, 0.55 mmol) and2-[2-(2-oxo-1-piperazinyl)ethyl]-1H-isoindole-1,3(2H)-dione (150 mg,0.55 mmol) in EtOH (2 mL) were stirred at 85° C. After 12 h, thesolution was concentrated and the residue purified via columnchromatography (silica, 0-8% MeOH in DCM (1% NH₄OH)) yielding the titlecompound (100 mg, 42%) as a light yellow solid: LCMS (ES) m/e 432(M+H)⁺.

(d)1-(2-aminoethyl)-4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone

To a solution of2-(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-oxo-1-piperazinyl}ethyl)-1H-isoindole-1,3(2H)-dione(100 mg, 0.232 mmol) in EtOH (2 mL) was added hydrazine hydrate (120 μL,3.85 mmol). After 2 h at 85° C., the solution was concentrated and theresidue purified by column chromatography (silica, 5-10% MeOH in DCM (1%NH₄OH)) yielding the title compound (46 mg, 66%) as a yellow oil: LCMS(ES) m/e 302 (M+H)⁺.

(e)6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-oxo-1-piperazinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

To a solution of1-(2-aminoethyl)-4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone(46 mg, 0.15 mmol) in DCM-EtOH (2 mL, 1:1) were added NaHCO₃ (32 mg,0.38 mmol) and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (29 mg,0.15 mmol). After 12 h, NaBH(OAc)₃ (38 mg, 0.15 mmol) was added. Afteran additional 2 h the solution was partitioned between NaHCO₃ (sat)-DCM.The aqueous phase was extracted several times with DCM and the combinedorganic fractions were dried (Na₂SO₄), concentrated and purified viacolumn chromatography (silica, 0-7% MeOH in DCM (1% NH₄OH)) yielding thetitle compound (48 mg, 67%) as a yellow solid: LCMS (ES) m/e 480 (M+H)⁺;¹H NMR (CD₃OD, 400 MHz) δ 8.44 (d, J=5.3 Hz, 1H), 8.12 (d, J=9.0 Hz,1H), 7.63 (d, J=7.8 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.8 Hz,1H), 6.96 (d, J=5.2 Hz, 1H), 4.21 (s, 2H), 4.19-4.22 (m, 2H), 4.03 (s,3H), 3.82 (s, 2H), 3.69-3.74 (m, 4H), 3.67 (s, 2H), 2.90-2.93 (m, 2H).

Example 12 Preparation of1-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone

The title compound (19.4 mg, 59 mmol) was prepared as a yellow solidaccording to Example 11, except substituting2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (12 mg, 0.073mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 451 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.44 (bs, 1H), 8.12 (d,J=8.9 Hz, 1H), 7.95 (s, 1H), 7.17 (d, J=9.0 Hz, 1H), 6.95 (bs, 2H),4.21-4.36 (m, 8H), 4.03 (s, 3H), 3.77 (s, 2H), 3.73 (s, 2H), 3.64-3.67(m, 2H), 2.85-2.89 (m, 2H).

Example 13 Preparation of6-{[(2-{1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

The title compound (62 mg, 22%) was prepared as a yellow foam accordingto Example 1, except substituting1,1-dimethylethyl[2-(4-piperidinyl)ethyl]carbamate (1 g, 4.38 mmol)[prepared according to Ambler, J.; et. al. Bioorg. Med. Chem. Lett.1999, 9, 9, 1317.] for1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate: LCMS (ES) m/e 483(M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J=4.9 Hz, 1H), 8.08 (d, J=9.0Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 7.04 (d, J=7.8Hz, 1H), 4.10-4.13 (m, 2H), 4.06 (s, 3H), 3.82 (s, 2H), 3.53 (s, 2H),3.34-3.37 (m, 2H), 2.71-2.75 (m, 2H), 1.82-1.85 (m, 2H), 1.51-1.63 (m,5H).

Example 14 Preparation of6-{[(2-{1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

The title compound (28 mg, 10%) was prepared as a yellow foam accordingto Example 1, except substituting1,1-dimethylethyl[2-(4-piperidinyl)ethyl]carbamate (1 g, 4.38 mmol)[prepared according to Ambler, J.; et. al. Bioorg. Med. Chem. Lett.1999, 9, 9, 1317.] for1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate as well as3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (105 mg,0.590 mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 467 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=4.9 Hz, 1H),8.09 (d, J=9.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H),6.99 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 4.07-4.13 (m, 2H), 4.06 (s, 3H),3.80 (s, 2H), 3.35-3.50 (m, 2H), 2.71-2.75 (m, 2H), 1.83-1.86 (m, 2H),1.52-1.63 (m, 5H).

Example 15 Preparation of6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

The title compound (100 mg, 32%) was prepared as a yellow solidaccording to Example 1, except substituting1,1-dimethylethyl[2-(4-piperidinyl)ethyl]carbamate (2 g, 8.77 mmol)[prepared according to Ambler, J.; et. al. Bioorg. Med. Chem. Lett.1999, 9, 9, 1317.] for1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate as well as4-bromo-3-fluoro-6-(methyloxy)quinoline (2.25 g, 8.77 mmol) for8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine: LCMS (ES) m/e 466(M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J=4.6 Hz, 1H), 7.87 (d, J=9.1Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.34 (dd,J=2.8, 6.3 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 3.97 (s, 3H), 3.86 (s, 2H),3.54 (s, 2H), 3.47-3.50 (m, 2H), 3.30-3.31 (m, 1H), 2.74-2.78 (m, 2H),1.87-1.91 (m, 2H), 1.65-1.68 (m, 3H), 1.53-1.56 (m, 3H).

Example 16 Preparation of6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

The title compound (100 mg, 33%) was prepared as a yellow solidaccording to Example 1, except substituting the following threereagents: 1,1-dimethylethyl[2-(4-piperidinyl)ethyl]carbamate (1 g, 4.38mmol) [prepared according to Ambler, J.; et. al. Bioorg. Med. Chem.Lett. 1999, 9, 9, 1317.] for1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate,4-bromo-3-fluoro-6-(methyloxy)quinoline (2.25 g, 8.77 mmol) for8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (117 mg,0.657 mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 482 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=4.5 Hz, 1H),7.87 (d, J=9.1 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.34 (dd, J=2.7, 6.3 Hz,1H), 7.29 (d, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 3.97(s, 3H), 3.79 (s, 2H), 3.35-3.50 (m, 2H), 3.26-3.30 (m, 2H), 2.71-2.75(m, 2H), 1.87-1.90 (m, 2H), 1.62-1.66 (m, 3H), 1.52-1.55 (m, 2H).

Example 17 Preparation of6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-hydroxy-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one(a) 2-[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]acetamide

A solution of ethyl[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]acetate (15g, 54.15 mmol) [prepared according to Caroon, J. M.; et al. J. Med.Chem. 1981, 24, 1320.] in 7N NH₃-MeOH (16 mL) was heated to 100° C. in asealed tube for 3d. The solution was cooled and concentrated and theresidue washed with DCM providing the title compound (4 g, 30%) as awhite solid which was used directly without further purification: LCMS(ES) m/e 249 (M+H)⁺.

(b) 4-(2-aminoethyl)-1-(phenylmethyl)-4-piperidinol

To a solution of LiAlH₄ (1.8 g, 0.048 mmol) in THF (40 mL) at 0° C. wasadded dropwise via addition funnel a solution of2-[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]acetamide (4 g, 0.016 mmol)in THF (40 mL). The solution warmed to 25° C. and was then heated toreflux for 12 h. After cooling, the solution was then carefully quenchedwith a saturated solution of sodium potassium tartrate and extractedseveral times with DCM. The combined organic fractions were dried(Na₂SO₄) and the resulting residue was used directly without furtherpurification: LCMS (ES) m/e 236 (M+H)⁺.

(c) 1,1-dimethylethyl{2-[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]ethyl}carbamate

To a solution of 4-(2-aminoethyl)-1-(phenylmethyl)-4-piperidinol (2.7 g,11.5 mmol) in THF/CH₃CN (57 mL, 1:1) was added Boc₂O dropwise. After 0.5h, the solution was concentrated and the residue purified via columnchromatography (silica, 2% MeOH in DCM (1% NH₄OH)) yielding the titlecompound (3.2 g, 83%) as a yellow oil: LCMS (ES) m/e 336 (M+H)⁺.

(d) 1,1-dimethylethyl[2-(4-hydroxy-4-piperidinyl)ethyl]carbamate

A solution of 1,1-dimethylethyl{2-[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]ethyl}carbamate (3.2 g, 9.5mmol) and Pd(OH)₂ (1.92 g, 60 wt %) in EtOH (50 mL) was hydrogenatedusing a Parr Shaker under 50 psi. After 12 h, the solution was filteredthrough Celite® and concentrated yielding the title compound (2.33 g,quant.) as a yellow oil: LCMS (ES) m/e 245 (M+H)⁺.

(e)6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-hydroxy-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

The title compound (60 mg, 21%) was prepared as a yellow solid accordingto Example 1, except substituting1,1-dimethylethyl[2-(4-hydroxy-4-piperidinyl)ethyl]carbamate (1.5 g,6.15 mmol) for 1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate aswell as 4-bromo-3-fluoro-6-(methyloxy)quinoline (1.57 g, 6.15 mmol) for8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine: LCMS (ES) m/e 498(M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.48 (d, J=4.7 Hz, 1H), 7.86 (d, J=9.1Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.39 (d, J=2.6 Hz, 1H), 7.34 (dd,J=2.7, 6.4 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 3.96 (s, 3H), 3.83 (s, 2H),3.56-3.60 (m, 2H), 3.52 (s, 2H), 3.26-3.29 (m, 2H), 2.87-2.91 (m, 2H),1.84-1.90 (m, 6H).

Example 18 Preparation of6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-hydroxy-4-piperidinyl}ethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

The title compound (71 mg, 26%) was prepared as a yellow solid accordingto Example 1, except substituting the following three reagents:1,1-dimethylethyl[2-(4-hydroxy-4-piperidinyl)ethyl]carbamate (1.5 g,6.15 mmol) [prepared according to Example 20] for1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate,4-bromo-3-fluoro-6-(methyloxy)quinoline (1.57 g, 6.15 mmol) for8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (100 mg,0.564 mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS(ES) m/e 482 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=4.6 Hz, 1H),7.87 (d, J=9.1 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.33 (dd, J=2.7, 6.3 Hz,1H), 7.28 (d, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.65 (s, 2H), 3.96(s, 3H), 3.81 (s, 3H), 3.55-3.61 (m, 2H), 3.26-3.29 (m, 2H), 2.88-2.91(m, 2H), 1.80-1.93 (m, 6H).

Example 19 Preparation of6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-piperidinyl}-2-hydroxyethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one(a) hydroxy[1-(phenylmethyl)-4-piperidinyl]acetonitrile

To a solution of 1-(phenylmethyl)-4-piperidinecarbaldehyde (2.35 g, 11.6mmol)[prepared according to Alfaro-Lopez, J.; et al. J. Med. Chem. 1999,42, 5359] in THF (160 mL) at 0° C. was added dropwise Et₂AlCN (25 mL, 1Msolution in toluene). After 1 h, the solution was partitioned betweenNaHCO₃(sat)-DCM. The aqueous phase was extracted several times with DCMand the combined organic fractions were dried (Na₂SO₄) and concentratedyielding the title compound as a yellow oil which was used directlywithout further purification: LCMS (ES) m/e 249 (M+H)⁺.

(b) 2-amino-1-[1-(phenylmethyl)-4-piperidinyl]ethanol

To a solution of LiAlH₄ (1.1 g, 28.7 mmol) in THF (25 mL) at 0° C. wasadded dropwise via addition funnel a solution ofhydroxy[1-(phenylmethyl)-4-piperidinyl]acetonitrile (2.2 g, 9.56 mmol)in THF (25 mL). After 12 h at 25° C., the solution was carefullyquenched by dropwise additional of sodium potassium tartrate andextracted several times with DCM. The combined organic fractions weredried (Na₂SO₄) and concentrated yielding the title compound as a yellowoil which was used without further purification: LCMS (ES) m/e 235(M+H)⁺.

(c) 1,1-dimethylethyl{2-hydroxy-2-[1-(phenylmethyl)-4-piperidinyl]ethyl}carbamate

To a solution of 2-amino-1-[1-(phenylmethyl)-4-piperidinyl]ethanol (2.2g, 9.4 mmol) in CH₃CN-THF (50 mL, 1:1) at 25° C. was added Boc₂O (2.4mL, 11.2 mmol). After 0.5 h, the solution was concentrated and theresidue purified via column chromatography (silica, 3-5% MeOH in DCM (1%NH₄OH)) yielding the title compound (2 g, 64%) as a yellow oil: LCMS(ES) m/e 335 (M+H)⁺.

(d) 1,1-dimethylethyl[2-hydroxy-2-(4-piperidinyl)ethyl]carbamate

A solution of 1,1-dimethylethyl{2-hydroxy-2-[1-(phenylmethyl)-4-piperidinyl]ethyl}carbamate (2 g, 5.97mmol) and Pd(OH)₂ (1.2 g, 60 wt %) in EtOH (30 mL) was hydrogenated at60 psi using a Parr Shaker. After 12 h, the solution was filteredthrough Celite® and concentrated affording the title compound as ayellow oil which was used directly without further purification: LCMS(ES) m/e 245 (M+H)⁺.

(e)6-{[(2-{1-[3-fluoro-6-(methyloxy)-4-quinolinyl]-4-piperidinyl}-2-hydroxyethyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

The title compound (10 mg, 16%) was prepared as a yellow solid accordingto Example 1, except substituting1,1-dimethylethyl[2-hydroxy-2-(4-piperidinyl)ethyl]carbamate (1.5 g,6.15 mmol) for 1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate aswell as 4-bromo-3-fluoro-6-(methyloxy)quinoline (1.57 g, 6.15 mmol) for8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine: LCMS (ES) m/e 498(M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J=4.5 Hz, 1H), 7.86 (d, J=9.1Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.33 (dd,J=2.7, 6.3 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 3.97 (s, 3H), 3.86 (ABquart., 2H), 3.60-3.65 (m, 1H), 3.53 (S, 2H), 3.49-3.53 (m, 1H),3.24-3.26 (m, 2H), 2.80-2.84 (m, 1H), 2.68-2.71 (m, 1H), 1.99-2.01 (m,1H), 1.67-1.70 (m, 5H).

Example Structure Formula 1

6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one2

6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one 3

6-{[(2-{4-[3-fluoro-6-(methyloxy)-4- quinolinyl]-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one4

6-{[(2-{4-[3-fluoro-6-(methyloxy)-4- quinolinyl]-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one 5

6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one6

6-{[(2-{4-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one 7

4-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4- yl]-2-piperazinone 8

6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin- 4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one9

6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin- 4-yl]-3-oxo-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one10

4-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2- piperazinone 11

6-{[(2-{4-[6-(methyloxy)-1,5-naphthyridin- 4-yl]-2-oxo-1-piperazinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one12

1-{2-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]ethyl}-4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2- piperazinone 13

6-{[(2-{1-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]-4-piperidinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one14

6-{[(2-{1-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]-4-piperidinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one15

6-{[(2-{1-[3-fluoro-6-(methyloxy)-4- quinolinyl]-4-piperidinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one16

6-{[(2-{1-[3-fluoro-6-(methyloxy)-4- quinolinyl]-4-piperidinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one17

6-{[(2-{1-[3-fluoro-6-(methyloxy)-4- quinolinyl]-4-hydroxy-4-piperidinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one18

6-{[(2-{1-[3-fluoro-6-(methyloxy)-4- quinolinyl]-4-hydroxy-4-piperidinyl}ethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]oxazin-3(4H)-one19

6-{[(2-{1-[3-fluoro-6-(methyloxy)-4- quinolinyl]-4-piperidinyl}-2-hydroxyethyl)amino]methyl}-2H- pyrido[3,2-b][1,4]thiazin-3(4H)-one

Example 20 Antimicrobial Activity Assay

Whole-cell antimicrobial activity was determined by broth microdilutionusing the National Committee for Clinical Laboratory Standards (NCCLS)recommended procedure, Document M7-A6, “Methods for DilutionSusceptibility Tests for Bacteria that Grow Aerobically”. The compoundswere tested in serial two-fold dilutions ranging from 0.016 to 16mcg/mL.

Compounds were evaluated against a panel of Gram-positive organisms,including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcuspyogenes, and Enterococcus faecalis.

In addition, compounds were evaluated against a panel of Gram-negativestrains including Haemophilus influenzae, Moraxella catarrhalis andEscherichia coli.

The minimum inhibitory concentration (MIC) was determined as the lowestconcentration of compound that inhibited visible growth. A mirror readerwas used to assist in determining the MIC endpoint.

One skilled in the art would consider any compound with a MIC of lessthan 20 mg/mL to be a potential lead compound. For instance, at least asubstantial majority of the listed Examples (1 to 19), as identified inthe present application, had a MIC ≦20 mg/ml against at least one of theorganisms listed above.

1. A compound of formula (I)

wherein: Z is CH or N; R is hydrogen or F; W₃ is CH; C(OH); or N; W₁,W₂, W₄, and W₅ are CH₂; or one of W₁, W₂, W₄, and W₅ is C═O and theothers are CH₂; A is CH₂ or CH(OH); R₁ is4H-Pyrido[3,2-b][1,4]thiazin-3-oxo-6-yl;4H-Pyrido[3,2-b][1,4]oxazin-3-oxo-6-yl; or2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, wherein Zis N.
 3. A compound according to claim 1, wherein R is F.
 4. A compoundaccording to claim 1, wherein W₃ is N.
 5. A compound according to claim1, wherein W₃ is CH.
 6. A compound according to claim 1, wherein W₃ isC(OH).
 7. A compound according to claim 1, wherein W₁, W₂, W₄, and W₅are CH₂.
 8. A compound according to claim 1, wherein one of W₁, W₂, W₄,and W₅ is C═O.
 9. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 10. Amethod of treating a bacterial infections selected from the groupconsisting of Staphylococcus aureus, Streptococcus pneumoniae,Streptococcus pyogenes, Enterococcus faecalis, Haemophilus influenzae,Moraxella catarrhalis and Escherichia coli, which comprisesadministering to a mammal in need thereof an effective amount of acompound according to claim 1.